Abstract Chronic Hepatitis C virus (HCV) infection is the leading cause of decompensated cirrhosis and hepatocellular carcinoma (HCC), which account for over 15,000 deaths annually in the US. The recent advancements of direct-acting antivirals (DAAs) offer greatly improved treatment outcomes with minimal side effects compared to the previous interferon (IFN) based regimen. Consequently, there has been a substantial increase in the number of patients undergoing antiviral therapy and in most cases, a sustained virological response (SVR) is attained. SVR has been believed to be a surrogate for successful clearance of HCV, which is defined by undetectable serum HCV RNA 12 weeks after the completion of antiviral therapy. Attaining SVR with DAA therapy is anticipated to terminate the necroinflammation of the liver, resulting in the amelioration of the liver function and the reduction of the risk of HCC. However, emerging evidence indicates that this risk reduction might not occur in all patients who achieved SVR with DAA. In fact, in a subset of this population, the liver disease continues to progress, and some patients even develop HCC despite having SVR. Therefore, it is of paramount importance to identify the high-risk post-SVR population and identify the underlying mechanism that promotes liver injury even after the clearance of HCV. We have recently uncovered that HCV continues to remain in the liver or peripheral blood mononuclear cells (PBMC) with the signatures of active viral replication despite persistently undetectable serum HCV RNA. This phenomenon is called ?occult HCV infection (OCI)? and is known to be extremely rare among the population who achieved SVR with IFN-based therapy. Of note, the current standard serum-based detection method widely used in clinical practice is incapable of detecting OCI. Thus, the clinical consequence of OCI has never been studied. Moreover, the prevalence of OCI has not been investigated in patients who attained SVR with DAA. Based on these notions, we developed an overarching hypothesis that ?OCI developed after SVR with DAA may lead to the deterioration of liver function and development of liver cancer.? Towards a better understanding of this emerging and potentially significant clinical entity, this study is designed to delineate both host and viral factors associated with the development of OCI. In addition, this study aims to establish a comprehensive diagnostic strategy of OCI. The successful completion of this proposal will refine the endpoint determination of antiviral therapy against HCV and revises clinical guidelines. Moreover, the insights obtained from this study will serve for the follow-up longitudinal cohort study that ultimately defines the prevalence and clinical significance of OCI in a rapidly growing population, post-SVR with DAA.